Comparison of a teratogenic transcriptome-based predictive test based on human embryonic versus inducible pluripotent...

Area of Science:

• Stem cell biology
• Developmental toxicology
• Genomics

Background:

• Human embryonic stem cells (hESCs) model early development for teratogenic hazard assessment.
• Ethical concerns surrounding hESC use necessitate alternative models.
• Human induced pluripotent stem cells (hiPSCs) are explored as a replacement for hESCs.

Purpose of the Study:

• To investigate the potential of hiPSCs to substitute hESCs in teratogenic hazard testing.
• To analyze transcriptome profiles during differentiation and in response to teratogens.
• To develop a robust method for hazard identification using stem cells.

Main Methods:

• Differentiated hiPSCs and hESCs for 14 days.
• Obtained and analyzed transcriptome profiles at day 0 and day 14.
• Exposed cells to valproic acid (VPA) during differentiation and analyzed gene expression changes.
• Calculated developmental potency (Dp) and developmental index (Di) to quantify teratogenic effects.

Main Results:

• Developmental genes showed significant variability (>70%) among cell lines but covered all three germ layers.
• Valproic acid (VPA) antagonized developmental gene expression across all cell lines (>90% gene variability).
• A uniform developmental index (Di) was achieved for VPA effects across hESCs and hiPSCs.

Conclusions:

• The developmental index (Di) provides a robust measure for teratogenic hazard identification.
• hiPSCs are a viable alternative to hESCs for developmental toxicology testing.
• The Di is a cell-type-independent metric for quantifying teratogen-induced developmental disruption.